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Azacitidina , Leucemia Mieloide Aguda , Humanos , Azacitidina/efectos adversos , Quimioterapia de Inducción/métodos , Pioglitazona/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Tretinoina/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Resultado del TratamientoRESUMEN
Acquired von Willebrand Syndrome (AVWS) is a rare coagulation disorder which can be associated with IgM paraproteinaemia. Recently, recombinant von Willebrand factor (rVWF) has become available for the treatment of bleedings in patients with inherited von Willebrand disease, but experience in patients with AVWS is limited. We report on 2 patients with AVWS with underlying IgM paraproteinaemia with distinct underlying pathomechanisms. In 1 patient, the paraprotein built unspecific complexes with von Willebrand factor (VWF). In the other patient, we were able to detect an IgM antibody against VWF. Bleeding in this patient was successfully treated with rVWF. To our knowledge, this is the first report about the successful use of rVWF in a patient with AVWS with the detection of a VWF-specific antibody.
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Paraproteinemias , Enfermedades de von Willebrand , Hemorragia/tratamiento farmacológico , Hemorragia/etiología , Humanos , Inmunoglobulina M/uso terapéutico , Paraproteinemias/diagnóstico , Enfermedades de von Willebrand/diagnóstico , Enfermedades de von Willebrand/tratamiento farmacológico , Factor de von Willebrand/uso terapéuticoRESUMEN
Spontaneous remission in acute lymphoblastic leukemia (ALL) is a rare phenomenon, which typically involves a pattern of feverish or septic disease followed by quick but mostly transient remission. We report on two male patients (46-year-old (pt. 1) and 19-year-old (pt. 2)) with CD20 positive, BCR-ABL negative common B-ALL. Patient 1 had received dexamethasone and cyclophosphamide (1.2 g) as a prephase therapy, followed by rituximab and a cumulative dose of 200 mg daunorubicin combined with 2 mg vincristine as an induction therapy. Patient 2 was treated with a reduced therapy regimen (Vincristine 1 mg, dexamethasone and 80 mg daunorubicin, 12-month mercaptopurine maintenance) due to (alcohol-related) toxic liver failure and pontine myelinolysis. Both patients developed severe septic disease just few days into induction treatment. Patient 1 suffered from pulmonary mycosis, which had to be resected eventually. Histological work-up revealed invasive mucor mycosis. Patient 2 presented with elevated serum aspergillus antigen and radiographic pulmonary lesions, indicative of pulmonary mycosis. In both patients, chemotherapy had to be interrupted and could not be resumed. Both patients recovered under broad antimicrobial, antifungal and prophylactic antiviral therapy and achieved molecular complete remission. At data cut-off remissions had been on-going for 34 months (pt. 1) and 8 years (pt. 2). Short-term, reduced intensity induction chemotherapy accompanied by severe fungal infections was followed by long-lasting continuous complete remissions in ALL. Thus, we hypothesize that infection-associated immunogenic responses may not only prevent early relapse of ALL but could also eradicate minimal residual disease. The effects of combined cytotoxic therapy and severe infection may also be mimicked by biomodulatory treatment strategies aiming at reorganizing pathologically altered cellular signaling networks. This could reduce toxicity and comorbidity in adult patients requiring leukemia treatment. Therefore, these two cases should encourage systematic studies on how leukemia stroma interaction can be harnessed to achieve long lasting control of ALL.
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Background: Most non-small cell lung cancers occur in elderly and frequently comorbid patients. Therefore, it is necessary to evaluate the efficacy of biomodulatory active therapy regimen, concertedly interfering with tumor-associated homeostatic pathways to achieve tumor control paralleled by modest toxicity profiles. Patients and Methods: The ModuLung trial is a national, multicentre, prospective, open-label, randomized phase II trial in patients with histologically confirmed stage IIIB/IV squamous (n = 11) and non-squamous non-small cell (n = 26) lung cancer who failed first-line platinum-based chemotherapy. Patients were randomly assigned on a 1:1 ratio to the biomodulatory or control group, treated with nivolumab. Patients randomized to the biomodulatory group received an all-oral therapy consisting of treosulfan 250 mg twice daily, pioglitazone 45 mg once daily, clarithromycin 250 mg twice daily, until disease progression or unacceptable toxicity. Results: The study had to be closed pre-maturely due to approval of immune checkpoint inhibitors (ICi) in first-line treatment. Thirty-seven patients, available for analysis, were treated in second to forth-line. Progression-free survival (PFS) was significantly inferior for biomodulation (N = 20) vs. nivolumab (N = 17) with a median PFS (95% confidence interval) of 1.4 (1.2-2.0) months vs. 1.6 (1.4-6.2), respectively; with a hazard ratio (95% confidence interval) of 1.908 [0.962; 3.788]; p = 0.0483. Objective response rate was 11.8% with nivolumab vs. 5% with biomodulation, median follow-up 8.25 months. The frequency of grade 3-5 treatment related adverse events was 29% with nivolumab and 10% with biomodulation. Overall survival (OS), the secondary endpoint, was comparable in both treatment arms; biomodulation with a median OS (95% confidence interval) of 9.4 (6.0-33.0) months vs. nivolumab 6.9 (4.6-24.0), respectively; hazard ratio (95% confidence interval) of 0.733 [0.334; 1.610]; p = 0.4368. Seventy-five percent of patients in the biomodulation arm received rescue therapy with checkpoint inhibitors. Conclusions: This trial shows that the biomodulatory therapy was inferior to nivolumab on PFS. However, the fact that OS was similar between groups gives rise to the hypothesis that the well-tolerable biomodulatory therapy may prime tumor tissues for efficacious checkpoint inhibitor therapy, even in very advanced treatment lines where poor response to ICi might be expected with increasing line of therapy.
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Invasive aspergillosis (IA) is a severe complication in immunocompromised patients. Early diagnosis is crucial to decrease its high mortality, yet the diagnostic gold standard (histopathology and culture) is time-consuming and cannot offer early confirmation of IA. Detection of IA by polymerase chain reaction (PCR) shows promising potential. Various studies have analysed its diagnostic performance in different clinical settings, especially addressing optimal specimen selection. However, direct comparison of different types of specimens in individual patients though essential, is rarely reported. We systematically assessed the diagnostic performance of an Aspergillus-specific nested PCR by investigating specimens from the site of infection and comparing it with concurrent blood samples in individual patients (pts) with IA. In a retrospective multicenter analysis PCR was performed on clinical specimens (n = 138) of immunocompromised high-risk pts (n = 133) from the site of infection together with concurrent blood samples. 38 pts were classified as proven/probable, 67 as possible and 28 as no IA according to 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group consensus definitions. A considerably superior performance of PCR from the site of infection was observed particularly in pts during antifungal prophylaxis (AFP)/antifungal therapy (AFT). Besides a specificity of 85%, sensitivity varied markedly in BAL (64%), CSF (100%), tissue samples (67%) as opposed to concurrent blood samples (8%). Our results further emphasise the need for investigating clinical samples from the site of infection in case of suspected IA to further establish or rule out the diagnosis.
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Aspergilosis/diagnóstico , Huésped Inmunocomprometido , Infecciones Fúngicas Invasoras/diagnóstico , Técnicas de Diagnóstico Molecular/normas , Reacción en Cadena de la Polimerasa/normas , Adolescente , Adulto , Anciano , Aspergilosis/sangre , Aspergilosis/microbiología , Aspergillus/aislamiento & purificación , Niño , Preescolar , Femenino , Humanos , Infecciones Fúngicas Invasoras/sangre , Infecciones Fúngicas Invasoras/microbiología , Masculino , Persona de Mediana Edad , Técnicas de Diagnóstico Molecular/métodos , Estudios Retrospectivos , Sensibilidad y Especificidad , Adulto JovenRESUMEN
Acute gastrointestinal (GI) graft-versus-host disease (GvHD) is a life-threating complication in patients after allogeneic stem cell transplantation (ASCT). In 60 sonographic analyses, a novel scoring system for non-invasive diagnosis of severe GI GvHD was developed. The score comprised morphological and vascular changes using B-mode and color-coded Doppler sonography, changes of mural stiffness using compound elastography, and dynamic microvascularisation using contrast-enhanced ultrasound (CEUS). Furthermore, inflammatory parameters such as CRP, Calprotectin, and regenerating islet-derived protein 3α (Reg3α) were obtained. ROC curve analysis of our novel GvHD sum score revealed an area under the curve of 1.0 (95% CI: 0.99-1.00) in diagnosing GI GvHD and 0.88 (95% CI: 0.79-0.96) for severe GI GvHD. A sum score above 5 correlated with GI GvHD with a sensitivity of 97.6% (41/42) and a specificity of 94.4% (17/18) and score values above 10 with severe GI GvHD with a sensitivity of 91.7% (11/12) and specificity of 79.2% (38/48). The additional use of inflammatory parameters did not improve the predictive power. CEUS is a promising, non-invasive tool for the diagnosis of acute GI GvHD. Together with further descriptive parameters for inflammatory processes, it gains significant diagnostic accuracy in identifying patients with severe stages of acute intestinal GvHD.
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Medios de Contraste/administración & dosificación , Ecocardiografía Doppler en Color , Diagnóstico por Imagen de Elasticidad , Enfermedad Injerto contra Huésped , Enfermedades Intestinales , Índice de Severidad de la Enfermedad , Enfermedad Aguda , Adulto , Anciano , Femenino , Enfermedad Injerto contra Huésped/sangre , Enfermedad Injerto contra Huésped/diagnóstico por imagen , Humanos , Enfermedades Intestinales/sangre , Enfermedades Intestinales/diagnóstico por imagen , Complejo de Antígeno L1 de Leucocito/sangre , Masculino , Persona de Mediana Edad , Proteínas Asociadas a Pancreatitis/sangreRESUMEN
BACKGROUND: Maintaining gastrointestinal (GI) microbiome diversity plays a key role during allogeneic stem cell transplantation (ASCT), and loss of diversity correlates with acute GI graft versus host disease (GvHD) and poor outcomes. METHODS: In this retrospective analysis of 161 ASCT patients, we used serial analyses of urinary 3-indoxyl sulfate (3-IS) levels and GI microbiome parameters within the first 10 days after ASCT to identify potential commensal microbiota-sparing antibiotics. Based on antibiotic activity, we formed 3 subgroups (Rifaximin without systemic antibiotics, Rifaximin with systemic antibiotics, and Ciprofloxacin/Metronidazole with/without systemic antibiotics). RESULTS: Mono-antibiosis with Rifaximin revealed higher 3-IS levels (P < .001), higher Clostridium cluster XIVa (CCXIVa) abundance (P = .004), and higher Shannon indices (P = .01) compared to Ciprofloxacin/Metronidazole with/without systemic antibiotics. Rifaximin followed by systemic antibiotics maintained microbiome diversity compared to Ciprofloxacin/Metronidazole with/without systemic antibiotics, as these patients showed still higher 3-IS levels (P = .04), higher CCXIVa copy numbers (P = .01), and higher Shannon indexes (P = .01). Even for this larger cohort of patients, the outcome was superior with regard to GI GvHD (P = .05) and lower transplant-related mortality (P < .001) for patients receiving Rifaximin plus systemic antibiotics compared to other types of systemic antibiotic treatment. Antibiosis with Ciprofloxacin/Metronidazole (n = 12, P = .01), Piperacillin/Tazobactam (n = 52, P = .01), Meropenem/Vancomycin (n = 16, P = .003), Ceftazidime (n = 10, P = .03), or multiple systemic antibiotics (n = 53, P = .001) showed significantly lower 3-IS levels compared to mono-antibiosis with Rifaximin (n = 14) or intravenous Vancomycin (n = 4, not statistically significant). CONCLUSIONS: Different types of antibiotic treatments show different impacts on markers of microbiome diversity. The identification of antibiotics sparing commensal bacteria remains an ongoing challenge. However, Rifaximin allowed a higher intestinal microbiome diversity, even in the presence of systemic broad-spectrum antibiotics.
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Antibacterianos/efectos adversos , Microbioma Gastrointestinal/efectos de los fármacos , Trasplante de Células Madre Hematopoyéticas , Adulto , Enfermedad Injerto contra Huésped/microbiología , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Trasplante HomólogoRESUMEN
Cutaneous manifestations in hematologic malignancies, especially in leukemia, are not common and may be very variable. Here we report a very unusual case of a patient (female, 70 years old) who was admitted to the hospital in 2016 because of skin lesions on the face, the trunk of the body and the extremities. She had a history of breast cancer in the year 2004 (pT1b, pN0, cM0, L0, V0, R0) which had been resected and treated with adjuvant radiation and chemotherapy (cyclophosphamide, methotrexate, 5-fluorouracile) as well as psoriasis treated with methotrexate and cyclosporine. Because of mild cytopenia a bone marrow aspirate/biopsy was performed showing myelodysplastic syndrome (MDS) with multilineage dysplasia. Cytogenetic review revealed a complex aberrant karyotype denoting adverse outcome. Simultaneously, a skin biopsy could confirm leukemic skin infiltration. Consequently, a therapy with azacitidine was started. After the first cycle the patient developed severe pancytopenia with a percentage of 13% peripheral blasts (previously 0-2%) as well as fever without evidence for infection which was interpreted as progressive disease. Therefore, the therapeutic regimen was changed to a biomodulatory therapy consisting of low-dose azacitidine 75 mg/day (given sc d1-7 of 28), pioglitazone 45 mg/day per os, and all-trans-retinoic acid (ATRA) 45 mg/m2/day per os. After cycle 1 of this combined biomodulatory therapy the patient showed hematologic recovery; besides a mild anemia (hemoglobin 11.1 g/dl) she developed a normal blood count. Moreover, the cutaneous leukemic infiltrates which had been unaffected by the azacitidine ameliorated tremendously after 2 cycles resulting in a complete remission of the skin lesions after cycle 6. In conclusion, we report a very unusual case with cutaneous infiltrates being the first clinical manifestation of hematologic disease, preceding the development of acute myeloid leukemia. While azacitidine alone was ineffective, a combined biomodulatory approach resulted in a complete remission of the cutaneous manifestation.
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In allogeneic stem cell transplantation (ASCT), systemic broad-spectrum antibiotics are frequently used for treatment of infectious complications, but their effect on microbiota composition is still poorly understood. This retrospective analysis of 621 patients who underwent ASCT at the University Medical Center of Regensburg and Memorial Sloan Kettering Cancer Center in New York assessed the impact of timing of peritransplant antibiotic treatment on intestinal microbiota composition as well as transplant-related mortality (TRM) and overall survival. Early exposure to antibiotics was associated with lower urinary 3-indoxyl sulfate levels (P < .001) and a decrease in fecal abundance of commensal Clostridiales (P = .03) compared with late antibiotic treatment, which was particularly significant (P = .005) for Clostridium cluster XIVa in the Regensburg group. Earlier antibiotic treatment before ASCT was further associated with a higher TRM (34%, 79/236) compared with post-ASCT (21%, 62/297, P = .001) or no antibiotics (7%, 6/88, P < .001). Timing of antibiotic treatment was the dominant independent risk factor for TRM (HR, 2.0; P ≤ .001) in multivariate analysis besides increase age (HR, 2.15; P = .004), reduced Karnofsky performance status (HR, 1.47; P = .03), and female donor-male recipient sex combination (HR, 1.56; P = .02) A competing risk analysis revealed the independent effect of early initiation of antibiotics on graft-versus-host disease-related TRM (P = .004) in contrast to infection-related TRM and relapse (not significant). The poor outcome associated with early administration of antibiotic therapy that is active against commensal organisms, and specifically the possibly protective Clostridiales, calls for the use of Clostridiales-sparing antibiotics and rapid restoration of microbiota diversity after cessation of antibiotic treatment.
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Antibacterianos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Trasplante de Células Madre/métodos , Adulto , Antibacterianos/efectos adversos , Clostridium/efectos de los fármacos , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Humanos , Infecciones/etiología , Infecciones/mortalidad , Masculino , Estudios Retrospectivos , Factores de Riesgo , Trasplante de Células Madre/efectos adversos , Trasplante de Células Madre/mortalidad , Análisis de Supervivencia , Tiempo de Tratamiento , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
Indole, which is produced from l-tryptophan by commensal bacteria expressing tryptophanase, not only is an important intercellular signal in microbial communities, but also modulates mucosal barrier function and expression of pro- and anti-inflammatory genes by intestinal epithelial cells. Here, we hypothesized that decreased urinary excretion of 3-indoxyl sulfate (3-IS), the major conjugate of indole found in humans, may be a marker of gut microbiota disruption and increased risk of developing gastrointestinal (GI) graft-versus-host-disease. Using liquid chromatography/tandem mass spectrometry, 3-IS was determined in urine specimens collected weekly within the first 28 days after allogeneic stem cell transplantation (ASCT) in 131 patients. Low 3-IS levels within the first 10 days after ASCT were associated with significantly higher transplant-related mortality (P = .017) and worse overall survival (P = .05) 1 year after ASCT. Least absolute shrinkage and selection operator regression models trained on log-normalized counts of 763 operational taxonomic units derived from next-generation sequencing of the hypervariable V3 region of the 16S ribosomal RNA gene showed members of the families of Lachnospiraceae and Ruminococcaceae of the class of Clostridia to be associated with high urinary 3-IS levels, whereas members of the class of Bacilli were associated with low 3-IS levels. Risk factors of early suppression of 3-IS levels were the type of GI decontamination (P = .01), early onset of antibiotic treatment (P = .001), and recipient NOD2/CARD15 genotype (P = .04). In conclusion, our findings underscore the relevance of microbiota-derived indole and metabolites thereof in mucosal integrity and protection from inflammation.
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Microbioma Gastrointestinal/fisiología , Enfermedad Injerto contra Huésped/microbiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Indicán/orina , Adulto , Anciano , Aloinjertos , Cromatografía de Fase Inversa , Femenino , Genotipo , Enfermedad Injerto contra Huésped/genética , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Proteína Adaptadora de Señalización NOD2/genética , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Single nucleotide polymorphisms (SNPs) within nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and toll-like receptor (TLR) 5 genes have been recently associated with the incidence and outcome of infections. In this study, we analyzed 38 patients with septic shock after allogeneic stem cell transplantation (allo-SCT) for an association of SNPs within NOD2 and TLR5 genes, with susceptibility to septic shock. One hundred twenty-seven transplant recipients unaffected by any infectious complications were used as controls. We found a significant association between the presence of donor NOD2 SNP13 (3016_3017insC) and the incidence of septic shock (P = .002). In multivariate analysis, donor NOD2 SNP13 appeared as an independent risk factor for the incidence of septic shock after allo-SCT. No association was found for recipient SNPs (NOD2 and TLR5) and donor NOD2 SNP8, SNP12, and TLR5-Stop SNP. Our results suggest that NOD2 SNP13 has an impact on the pathophysiology of severe infectious complications and is an independent risk factor for the development of septic shock after allo-SCT.
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Trasplante de Células Madre Hematopoyéticas/métodos , Proteína Adaptadora de Señalización NOD2/genética , Choque Séptico/genética , Choque Séptico/metabolismo , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Trasplante Homólogo , Adulto JovenRESUMEN
INTRODUCTION: Irreversible electroporation (IRE) is a new minimally invasive tumor ablation technique which induces irreversible disruption of cell membrane integrity by changing the transmembrane potential resulting in cell death. Irreversible electroporation is currently undergoing clinical investigation as local tumor therapy for malignant liver and lung lesions. This is the first case report to describe the successful palliative ablation of a presacral recurrence of an endometrial cancer to achieve locoregional tumor control and pain relief. CASE PRESENTATION: A 56-year-old Caucasian woman was referred for interventional treatment of an advanced local recurrence of endometrial cancer (11.9 × 11.6 × 14.9cm) with infiltration of the sacral bone and nerve plexus. Due to the immediate proximity to the sacral plexus, the patient could neither undergo surgical therapy nor a second radiation therapy. Due to its ablation mechanism irreversible electroporation was deemed to be the best therapy option. CONCLUSION: We showed in this case that a large tumor mass adjacent to a bundle of neural structures, the sacral plexus, can be widely ablated by irreversible electroporation with only minor temporary impairment of the neural function, even though a large infiltrating tissue volume (941cm3) was ablated.
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Carbon fiber-reinforced polyetheretherketone (CF/PEEK) is a thermoplastic composite biomaterial exhibiting properties suitable for load-bearing orthopedic implants. However, the hydrophobic surface of CF/PEEK implants induces the deposition of a peri-implant fibrous tissue capsule preventing bone apposition. However, if bone apposition was improved, the use of CF/PEEK in orthopedics could be increased as it has many advantages compared with metallic implants. In this study, CF/PEEK screws were coated with titanium (Ti) using two different techniques, namely vacuum plasma spraying (VPS) and physical vapor deposition (PVD) with uncoated screws as controls. These coatings were characterized and implanted in a loaded sheep tibia model. In the characterization of the screw surfaces using microscopy techniques, the uncoated screws were seen to have an irregular surface. The PVD coating appeared smooth and consistent, whereas the VPS coating appeared to be a rough coating with some inhomogeneities, which did not cover the entire surface area. Nevertheless, in the ex vivo analysis the VPS-coated screws had a screw removal torque which was statistically greater than uncoated and PVD-coated screws (p ≤ 0.002 for both comparisons). Additionally, the VPS-coated screws had a statistically higher bone contact area than the uncoated screws (p = 0.006), whereas no statistical difference was detected between VPS and PVD coating types (p = 0.11). Thereby illustrating that Ti coating of CF/PEEK screws significantly improve bone apposition and removal torque compared with uncoated CF/PEEK screws.
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Tornillos Óseos , Huesos/efectos de los fármacos , Carbono/química , Materiales Biocompatibles Revestidos , Cetonas/química , Polietilenglicoles/química , Prótesis e Implantes , Titanio/química , Animales , Benzofenonas , Fibra de Carbono , Femenino , Fijadores Internos , Ensayo de Materiales , Polímeros , Diseño de Prótesis , Ovinos , Propiedades de Superficie , Tibia/patología , Torque , Soporte de PesoRESUMEN
BACKGROUND: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is often performed in cases of advanced hematological diseases, but because of the associated mortality and a high risk of relapse it is life prolonging only in some patients. PATIENTS AND METHODS: A retrospective multi-center analysis of 401 patients was conducted to analyze the variables associated with outcome after alloHSCT in advanced hematological diseases. The Cox proportional hazards model was used to assess the independence of overall survival (OS) and disease-free survival (DFS) from prognostic factors in a multivariate model. RESULTS: The 5-year OS and DFS were 27.3 and 21.1% respectively. Multivariate analysis showed that the underlying malignancy had a significant influence on OS and DFS (p < 0.001 and p < 0.011, respectively), whereas development of severe acute graft versus host disease (GvHD) had a negative impact on OS (p < 0.001). Development of chronic GvHD showed a trend to a better OS (p = 0.085) and DFS (p = 0.199). No impact was seen for the intensity of conditioning. CONCLUSION: Development of chronic GvHD but not the conditioning regimen improved the outcome after alloHSCT for advanced malignancies, underlining the importance of immunological rather than cytotoxic effects.
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Enfermedad Injerto contra Huésped/mortalidad , Enfermedades Hematológicas/mortalidad , Enfermedades Hematológicas/cirugía , Trasplante de Células Madre Hematopoyéticas/mortalidad , Complicaciones Posoperatorias/mortalidad , Adolescente , Adulto , Enfermedad Crónica , Comorbilidad , Femenino , Alemania/epidemiología , Supervivencia de Injerto , Humanos , Técnicas In Vitro , Incidencia , Masculino , Persona de Mediana Edad , Prevalencia , Factores de Riesgo , Análisis de Supervivencia , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Depletion of host Langerhans cells (LCs) prevents cutaneous graft-versus-host disease (GvHD) in mice. We analyzed whether UVB irradiation is tolerated during the course of human allogeneic hematopoietic cell transplantation and whether depletion of LCs by broadband UVB could improve GvHD outcome. A total of 17 patients received six whole-body UVB irradiations with 75% of the individually determined minimal erythemal dose after conditioning with a reduced intensity protocol. LCs, dermal dendritic cells (DCs), and macrophages were analyzed before and after UVB irradiation by immunohistochemical analysis. Circulating blood cells and serum factors were analyzed in parallel. In striking contrast to previous data, our irradiation protocol was well tolerated in all patients. UVB treatment decreased the number of LCs and also affected dermal DCs. UVB-treated patients also had significantly higher 25-hydroxyvitamin D3 serum levels and higher numbers of circulating CD4+ FoxP3+ regulatory T cells. Strikingly, nine out of nine patients with complete LC depletion (<1 LC per field) developed only grade I GvHD or no GvHD up to day 100. Our results strongly suggest that prophylactic UVB irradiation post transplant is safe and should be further explored as a clinical strategy to prevent acute (skin) GvHD.
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Enfermedad Injerto contra Huésped/prevención & control , Efecto Injerto vs Leucemia , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Irradiación Corporal Total/métodos , Enfermedad Aguda , Adulto , Animales , Enfermedad Crónica , Terapia Combinada , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Humanos , Células de Langerhans/inmunología , Masculino , Ratones , Persona de Mediana Edad , Dosis de Radiación , Especificidad de la Especie , Acondicionamiento Pretrasplante/métodos , Trasplante HomólogoRESUMEN
BACKGROUND: Recent studies using sheep critical sized defect models to test tissue engineered products report high morbidity and complications rates. This study evaluates a large bone defect model in the sheep tibia, stabilized with two, a novel Carbon fibre Poly-ether-ether-ketone (CF-PEEK) and a locking compression plate (LCP) which could sustain duration for up to 6 month with an acceptable low complication rate. METHODS: A large bone defect of 3 cm was performed in the mid diaphysis of the right tibia in 33 sheep. The defect was stabilised with the CF - PEEK plate and an LCP. All sheep were supported with slings for 8 weeks after surgery. The study was carried out for 3 months in 6 and for 6 months in 27 animals. RESULTS: The surgical procedure could easily be performed in all sheep and continuous in vivo radiographic evaluation of the defect was possible. This long bone critical sized defect model shows with 6.1% a low rate of complications compared with numbers mentioned in the literature. CONCLUSIONS: This experimental animal model could serve as a standard model in comparative research. A well defined standard model would reduce the number of experimental animals needed in future studies and would therefore add to ethical considerations.
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Placas Óseas , Fijación Interna de Fracturas/instrumentación , Fijación Interna de Fracturas/métodos , Tibia/cirugía , Alternativas al Uso de Animales , Animales , Benzofenonas , Materiales Biocompatibles/efectos adversos , Carbono , Diáfisis/diagnóstico por imagen , Diáfisis/lesiones , Diáfisis/cirugía , Modelos Animales de Enfermedad , Curación de Fractura/efectos de los fármacos , Curación de Fractura/fisiología , Cetonas/efectos adversos , Longevidad/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Osteogénesis/fisiología , Polietilenglicoles/efectos adversos , Polímeros , Complicaciones Posoperatorias , Diseño de Prótesis , Radiografía , Ovinos , Tibia/diagnóstico por imagen , Tibia/lesionesRESUMEN
BACKGROUND: Pulmonary invasive fungal infections (IFI) are well-recognized complications with high morbidity and mortality in patients with hematologic malignancies. PATIENTS AND METHODS: Aerosolized liposomal amphotericin B (lipAmB) was evaluated as an antifungal prophylaxis in patients with an expected neutropenia of more than 10 days due to intensive chemotherapy or stem cell transplantation, in a prospective phase II trial. RESULTS: 98 treatment episodes were included in the study and compared to 105 historical control patients. Inhalation was performed between 0 and 103 days. No severe side effects of therapy occurred. 40 patients considered inhalations as unpleasant, 2 as very unpleasant, mostly due to bad taste or cough. Few cases of definite or probable IFI were recorded, whereas a large number of patients were treated with systemic antifungal therapy for pneumonia or fever of unknown origin without a significant difference between study patients and controls. In a predefined subgroup analysis of 48 patients with newly diagnosed acute myeloid leukemia (AML), significantly more patients survived for 1 year in the AmB prophylaxis than in the control group (80% vs. 54%, p < 0.01). CONCLUSIONS: Inhalations of lipAmB are feasible and safe. Results in the subgroup of patients with AML together with data from other trials suggest further evaluation of effectiveness.
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Anfotericina B/administración & dosificación , Enfermedades Pulmonares Fúngicas/etiología , Enfermedades Pulmonares Fúngicas/prevención & control , Neutropenia/complicaciones , Neutropenia/tratamiento farmacológico , Antifúngicos/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Allogeneic stem cell transplantation (ASCT) after reduced-intensity conditioning has become a reasonable treatment option for patients with advanced myelofibrosis. The role of characteristic molecular genetic abnormalities, such as JAK2V617F on outcome of ASCT, is not yet elucidated. In 139 of 162 myelofibrosis patients with known JAK2V617F mutation status who received ASCT after reduced-intensity conditioning, the impact of JAK2 genotype, JAK2V617F allele burden, and clearance of mutation after ASCT was evaluated. Overall survival was significantly reduced in multivariate analysis in patients harboring JAK2 wild-type (hazard ratio = 2.14, P = .01) compared with JAK2 mutated patients. No significant influence on outcome was noted for the mutated allele burden analyzed either as continuous variable or after dividing into quartiles. Achievement of JAK2V617F negativity after ASCT was significantly associated with a decreased incidence of relapse (hazard ratio = 0.22, P = .04). In a landmark analysis, patients who cleared JAK2 mutation level in peripheral blood 6 months after ASCT had a significant lower risk of relapse (5% vs 35%, P = .03). We conclude that JAK2V617F-mutated status, but not allele frequency, resulted in an improved survival and rapid clearance after allografting reduces the risk of relapse.
Asunto(s)
Janus Quinasa 2/genética , Mutación , Mielofibrosis Primaria/cirugía , Trasplante de Células Madre , Adulto , Anciano , Alelos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mielofibrosis Primaria/terapia , Recurrencia , Análisis de Supervivencia , Acondicionamiento Pretrasplante , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Mesenchymal stem cells (MSCs) represent an attractive cell population for the regeneration of mesenchymal tissues. Their special immunological characteristics suggest that MSCs could be used in nonautologous applications. In this study, the regenerative capacity of human and ovine MSCs was assessed in an ovine critical size defect model. Human and ovine MSCs from bone marrow were cultured on mineralized collagen and implanted into a 3.0-cm-long sheep tibia bone defect (n = 7). Unloaded mineralized collagen served as control. Bone healing was assessed until euthanasia 26 weeks after surgery by radiology and histologically after euthanasia. The presence of human cells after xenogenic transplantation was analyzed using human-specific in situ hybridization. Both radiology and histology demonstrated significantly better bone formation after transplantation of autologous ovine MSCs on mineralized collagen compared with unloaded matrices and with the xenogenic treatment group. Nevertheless, no local or systemic rejection reactions could be observed after transplantation of human MSCs, although the presence of human MSCs could be demonstrated. It can be concluded that despite successful demonstration of the presence of human MSCs after xenogenic transplantation, the xenogenic transplantation of human MSCs leads to poorer bone regeneration than autologous transplantation of ovine MSCs.
Asunto(s)
Regeneración Ósea , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Osteogénesis , Fracturas de la Tibia/terapia , Adulto , Animales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ovinos , Fracturas de la Tibia/metabolismo , Fracturas de la Tibia/patología , Trasplante HeterólogoRESUMEN
Toxicity-reduced conditioning is being used for allogeneic stem cell transplantation in older and/or comorbid patients. We report on the treatment of 133 patients (median age: 55.6 years [23-73 years]) with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS; n = 81), myeloproliferative syndromes (MPS; n = 20), and lymphoid malignancies (n = 32) using conditioning with FBM: fludarabine (5 x 30 mg/m(2)), 1,3-bis(2-chloroethyl)-1-nitrosourea (or carmustine, BCNU; 2 x 200 mg/m(2)), and melphalan (140 mg/m(2)). Patients 55 years or older received fludarabine with reduced BCNU (2 x150 mg/m(2)) and melphalan (110 mg/m(2)). After engraftment, chimerism analyses revealed complete donor hematopoiesis in 95.7% of patients. With a median follow-up of 58.5 months, 3- and 5-year overall survival (OS) was 53.0% and 46.1%, event-free survival (EFS) was 46.4% and 41.9%. No significant differences in OS and EFS were evident considering disease status (early vs advanced), patient age (<55 vs> or =55 years), or donor type (related vs unrelated) in univariate and multivariate analyses. The cumulative 5-year incidence of death due to relapse was 20.1%. Nonrelapse mortality (NRM) after 100 days and 1 year was 15.8% and 26.3%. Among patients with AML/MDS, advanced cases (n = 64, including 61 with active disease) showed an OS of 44.6% and 42.4% after 3 and 5 years, respectively. Therefore, FBM conditioning combines effective disease control with low NRM.